Allergic disorders, including allergic rhinitis, asthma, atopic dermatitis, food allergy and anaphylaxis are an increasingly common cause of morbidity in developed countries and, in the case of asthma and anaphylaxis, a not infrequent cause of death. All of these disorders are mediated, to some extent, by immediate hypersensitivity reactions in which the activation of inflammatory cells by the crosslinking of immunoglobulin (Ig) Fc receptors (R) leads rapidly to the release of vasoactive mediators, such as histamine and platelet activating factor (PAF), cytokines and proteolytic enzymes. Such immediate hypersensitivity reactions are the critical pathogenic mechanism in anaphylaxis and IgE-mediated food allergy and an important contributing mechanism in asthma, atopic dermatitis and allergic rhinitis. In both humans and mice, immediate hypersensitivity reactions can be mediated by antigen crosslinking of antigen-specific IgE bound to the high affinity IgE receptor, FcεRI, on mast cells and basophils, while the crosslinking of FcγRIII or FcγRIV on macrophages, neutrophils, and/or basophils by IgG/antigen complexes can mediate immediate hypersensitivity in mice and possibly also in humans.
Although some of these allergic disorders can be treated pharmacologically, manipulation of the immune system by administering increasing doses of allergen over time can also be an efficacious, albeit sometimes risky, way to suppress disease. Two different general strategies of allergen immunotherapy have been widely used. Standard immune desensitization involves administration of increasing doses of allergen through a subcutaneous, oral, rectal or sublingual route over a period of weeks to months. This procedure suppresses IgE-mediated disease through at least two mechanisms: 1) increased production of IgG antibodies that can activate an inhibitory Ig receptor, FcγRIIb, and intercept antigen before it can access mast cell and basophil IgE; and 2) induction of regulatory T cells, that can suppress production of IgE. Rapid desensitization procedures, in contrast, administer increasing concentrations of allergen over a period of hours or days. This time period is too short to work by altering Ig production; however, the precise mechanisms are not established. Unlike conventional desensitization, the suppressive effects of rapid desensitization can be quickly lost when allergen administration is discontinued.
To date, rapid desensitization techniques have always involved the administration of allergen. Although effective, this can be of limited utility in individuals who are allergic to multiple antigens. In addition, the presence of serum antibodies, including IgG, which can bind inoculated allergens, may make rapid desensitization more risky if the initial, small allergen doses are neutralized before they can access mast cell or basophil bound IgE, so that the first dose of allergen that interacts with cell-bound IgE is sufficiently large to induce a severe reaction. It has now been found that although administration of a single large dose of the anti-FcεRIα mAb, MAR-1, the anti-IgE mAb, EM-95, or the anti-FcγRIIb/RIII mAb, 2.4G2, can induce an anaphylactic response, administration of sequentially increasing doses of any of these mAbs, starting with a dose too small to induce detectable disease, as in rapid desensitization with allergen, inhibits IgE- or IgG-mediated immediate hypersensitivity. The results of these studies in a mouse model demonstrate the feasibility of this approach.
These and additional objects, embodiments, and aspects of the invention will become apparent by reference to the Figures and Detailed Description below.